The present invention relates to a pharmaceutical composition containing a sulfonamide derivative having an oxadiazole ring as an active ingredient for treating or preventing cancer.
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active site, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 to MMP-23, have been reported.
An MMP inhibitor has been developed as an anticancer agent as described in Chem. Rev. 1999, 99, 2735-2776, Current Pharmaceutical Design, 1999, 5, 787-819, etc.
It is described in CANCER RESEARCH 53, 878-883, 1993, CANCER RESEARCH 53, 5365-5369, 1993, etc. that an activity of MMP-2 and MMP-9 is enhanced in cancer patients.
It is well-known that MMP-9 is produced from immune cells such as macrophages and lymphocytes, and its production is controlled by cytokines in The Journal of Immunology 4159-4165, 1996 and The Journal of Immunology 2327-2333, 1997. This MMP-9 is thought to participate when a cell such as macrophage and lymphocyte destroys an extracellular matrix to wander around inflammation or tumor sites. Accordingly, it is supposed that a strong inhibition of MMP-9 may decrease immune response.
A sulfonamide derivative having an oxadiazole ring exhibits an MMP inhibitory activity as described in WO99/04780.
Further, there are other sulfonamide derivatives exhibiting an MMP inhibitory effect.
As described above, compounds exhibiting an MMP inhibitory activity are under development as an anticancer agent. However, the development of MMP inhibitor having more safety and high efficacy as medicaments has been desired.
In the above situation, the inventors of the present invention have found that certain sulfonamide derivatives having an oxadiazole ring are useful as an anticancer agent with safety and high efficacy.
The present invention relates to:
1) A pharmaceutical composition for treating or preventing cancer containing a compound of the general formula (I), a prodorug, a pharmaceutically acceptable salt, or a solvate thereof as an active ingredient: 
xe2x80x83wherein
R1 is NHOH, hydroxy, or lower alkyloxy;
R2 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R3 is hydrogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R4 is optionally substituted arylene or optionally substituted heteroarylene;
R5is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted non-aromatic heterocyclic group.
In more detail, the invention relates to the following 2) to 6).
2) A compound of the formula (Ixe2x80x2): 
xe2x80x83wherein
R6 is NHOH, hydroxy, or lower alkyloxy;
R7 is hydrogen, methyl, isopropyl, isobutyl, benzyl, or indol-3-ylmethyl;
R8 is hydrogen or optionally substituted lower alkyl;
R9is phenylene or 2,5-thiophene-diyl;
R10 is optionally substituted thienyl, optionally substituted furyl, or optionally substituted pyridyl;
a prodorug, or a pharmaceutically acceptable salt, or a solvate thereof.
3) A compound of the following formula: 
xe2x80x83a prodrug, or a pharmaceutically acceptable salt, or a solvate thereof.
4) A parmaceutical composition which contains a compound as described in 2) or 3) as an active ingredient.
5) A parmaceutical composition of 4) as an agent for treating or preventing cancer.
6) A parmaceutical composition of 4) as an agent for preventing metastasis.
7) Use of a compound of 2) or 3) for the preparation of medicine for treating cancer.
8) A method for treating a mammal cancer by administering to a mammal, including human, a therapeutic effective amount of the compound as described in 2) or 3).
In the present specification, the term xe2x80x9clower alkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
In the present specification, the term xe2x80x9clower alkenylxe2x80x9d means a straight- or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more double bond. Examples of the alkenyl include vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like. C2 to C6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.
In the present specification, the term xe2x80x9clower alkynylxe2x80x9d means a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and one or more triple bond. The alkynyl may contain (a) double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2 to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.
In the present specification, the term xe2x80x9ccycloalkylxe2x80x9d includes cycloalkyl group having 3 to 8 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C3 to C6 cycloalkyl is preferred.
In the present specification, the term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Examples include phenyl, 1-naphtyl, 2-naphtyl, anthryl, and the like.
In the present specification, the term xe2x80x9caralkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d substituted one or more with the above mentioned xe2x80x9carylxe2x80x9d at any possible position. Examples of the aralkyl are benzyl, phenethyl (e.g., 2-phenethyl), phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl), anthrylmethyl (e.g., 9-anthrylmethyl), and the like. Benzyl and phenylethy are preferred.
Preferable is benzyl as xe2x80x9caralkylxe2x80x9d for R2 or R3.
In the present specification, the term xe2x80x9cheteroarylxe2x80x9d employed alone or in combination with other terms includes a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with cycloalkyl, aryl, non-aromatic heterocyclic group, and other heteroaryl at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl(e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g., 2-indolizinyl, 6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), puriyl (e.g., 8-puriyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 3-quinolyl, 5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g., 2-naphthyridinyl), quinolanyl (e.g., 2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g., 2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), benzothienyl (e.g., 2-benzothienyl) and the like.
Preferable are indolyl and imidazolyl as xe2x80x9cheteroarylxe2x80x9d for R2.
Preferable are thienyl, pyridyl, dibenzofuranyl, isoxazolyl, tetrazolyl, and pyrolyl as xe2x80x9cheteroarylxe2x80x9d for R5. More preferable is 2-thienyl.
In the present specification, the term xe2x80x9cheteroarylalkylxe2x80x9d herein used includes the above mentioned xe2x80x9clower alkylxe2x80x9d substituted one or more with the above mentioned xe2x80x9cheteroarylxe2x80x9d at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), benzothiazolylmethyl (e.g., (benzothiazol-2-yl)methyl), indolylmethyl (e.g., indol-3-ylmethyl), imidazolylmethyl (e.g., imidazole-5ylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), indazolylmethyl (e.g., 1-indazolylmethyl), benzotriazolylmethyl (e.g., 1-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 4-pyridylmethyl), and the like.
Preferable are indol-3-ylmethyl and imidazol-5-ylmethyl as xe2x80x9cheteroarylalkylxe2x80x9d for R2.
In the present specification, the term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d employed alone or in combination with other terms includes a 5 to 7 membered non-aromatic ring which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a condensed ring which are formed with two or more of the non-aromatic ring. Examples of the non-aromatic heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g., 2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidinyl (piperidino, 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl (e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl), 4H-1,2,4-oxazol-5-one, 1,2,3,4-teterahydro-1,8-naphthyridine, and the like.
Preferable are pyrazolidinyl, piperidinyl, pyrrolinyl, and morpholinyl as xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d for R5.
In the present specification, the term xe2x80x9carylenexe2x80x9d herein used means a divalent group of the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the arylene are phenylene naphthylene, and the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-phenylen, 1,4-phenylene, and the like. Preferable is 1,4-phenylene.
In the present specification, the term xe2x80x9cheteroarylenexe2x80x9d herein used means a divalent group of the above-mentioned xe2x80x9cheteroarylxe2x80x9d. Examples of the heteroarylene are thionphene-diyl, furan-diyl, pyridine-diyl, and the like. Mentioned in more detail, it is exemplified by 2,5-thionphene-diyl, 2,5-furan-diyl, and the like. Preferable is 2,5-thionphene-diyl.
In the present specification, the term xe2x80x9clower alkyloxyxe2x80x9d herein used are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, and the like. Preferable are methyloxy, ethyloxy, n-propyloxy, isopropyloxy, and n-butyloxy. More preferable are methyloxy and ethyloxy.
In the present specification, the term xe2x80x9cacylxe2x80x9d employed alone or in combination with other terms includes alkylcarbonyl in which alkyl group is the above-mentioned xe2x80x9clower alkylxe2x80x9d and arylcarbonyl in which aryl group is the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, propyonyl, benzoyl, and the like. xe2x80x9cLower alkylxe2x80x9d and xe2x80x9carylxe2x80x9d may be substituted respectively with substituents mentioned below.
In the present specification, the term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo. Fluoro, chloro, and bromo are preferred.
In the present specification, the term xe2x80x9clower alkylthioxe2x80x9d herein used are methylthio, ethylthio, and the like.
In the present specification, the term xe2x80x9clower alkyloxycarbonylxe2x80x9d herein used are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, and the like.
In the present specification, the term xe2x80x9chalo(lower)alkylxe2x80x9d employed alone or in combination with other terms includes the above-mentioned xe2x80x9clower alkylxe2x80x9d which is substituted with the above mentioned xe2x80x9chalogenxe2x80x9d at 1 to 8 positions, preferably, at 1 to 5. Examples of the halo(lower)alkyl are trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, and the like. Preferable is trifluoromethyl.
In the present specification, examples of the term xe2x80x9chalo(lower)alkyloxyxe2x80x9d herein used are trifluoromethyloxy and the like.
In the present specification, examples of the term xe2x80x9clower alkylsulfonylxe2x80x9d herein used are methylsulfonyl, ethylsulfonyl and the like. Preferable is methylsulfonyl.
In the present specification, examples of the term xe2x80x9cacyloxyxe2x80x9d herein used are acetyloxy, propionyloxy, benzoyloxy and the like.
In the present specification, the term xe2x80x9csubstituted aminoxe2x80x9d employed alone or in combination with other terms includes amino substituted with one or two of the above mentioned xe2x80x9clower alkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cacylxe2x80x9d. Examples of the optionally substituted amino are methylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, acetylamino, benzoylamino and the like. Preferable are methylamino, dimethylamino, ethylmethylamino, diethylamino and acetylamino.
In the present specification, examples of the term xe2x80x9csubstituted aminocarbonylxe2x80x9d herein used are methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, diethylaminocarbonyl and the like. Preferable is diethylaminocarbonyl.
In the present specification, the substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d are cycloalkyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryloxy (e.g., phenyloxy), aralkyloxy (e.g., benzyloxy), lower alkylsulfonyl, guanidino, azo group, optionally substituted ureide (e.g., ureide, Nxe2x80x2-methylureide) and the like. These substituents are able to locate at one or more of any possible positions.
In the present specification, the substituents of xe2x80x9coptionally substituted arylenexe2x80x9d, xe2x80x9coptionally substituted heteroarylenexe2x80x9d, xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d, xe2x80x9coptionally substituted heteroaryl alkylxe2x80x9d, xe2x80x9coptionally substituted thienylxe2x80x9d, xe2x80x9coptionally substituted pyridylxe2x80x9d, and xe2x80x9coptionally substituted furylxe2x80x9d herein used are optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionally substituted ureide (e.g., ureide, Nxe2x80x2-methylureide) and the like. These substituents are able to locate at one or more of any possible positions.
Preferable are unsubstituted ones of xe2x80x9coptionally substituted arylenexe2x80x9d and xe2x80x9coptionally substituted heteroarylenexe2x80x9d for R4. These substituents are halogen, nitro, cyano, lower alkyloxy, and the like.
Preferred substituents of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, and xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d for R5 are lower alkyl, hydroxy(lower)alkyl, hydroxy, lower alkyloxy, lower alkylthio, halogen, nitro, carboxy, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, and the like. More preferred substituents are halogen and lower alkyl.
Preferable are unsubstituted aryl and substituted aryl with halogen or lower alkyl as xe2x80x9coptionally substituted arylxe2x80x9d for R5.
Preferred substituents of xe2x80x9coptionally substituted thienylxe2x80x9d, xe2x80x9coptionally substituted pyridylxe2x80x9d, and xe2x80x9coptionally substituted furylxe2x80x9d for R10 are lower alkyl and halogen.
Preferable are 2-thienyl or 2-thienyl substituted with lower alkyl or halogen at position for R10 of the general formula (Ixe2x80x2).
Preferable is a compound of the general formula (Ixe2x80x2) wherein R6 is hydroxy, R7 is methyl or isopropyl, R8 is hydrogen, R9 is 2,5-phenylene, R10 is hydroxy, non-substituted phenyl, or phenyl substituted with halogen or lower alkyl at 4 position.
Compounds (I) of the invention are able to be synthesized in accordance with the procedure described in WO97/27174 or as follows. 
wherein R2, R4, and R5 are as defined above, Hal is halogen, R11 is protecting group of carboxy.
(Step 1)
This step is a process of obtaining a sulfonamide derivative (IV) from a compound (II) as a starting material. The process may be carried out in accordance with the same procedure as (Method A-Step 1) in WO97/27174.
(Step 2)
This step is a process of constructing an oxadiazole ring by the reaction of a compound (IV) and a compound (V).
A compound (IV) is dissolved in diglyme and toluene, etc., and then to the reaction mixture are added oxalyl chloride and N,N-dimethylformamide at 0 to 30xc2x0 C., preferably 0 to 20xc2x0 C., and then the reaction mixture is stirred preferably for 60 to 120 min. To a solution of a compound (V) and pyridine in diglyme and toluene is added the solution of acyl chloride prepared above under ice-cooling, and then the reaction mixture is stirred at 0 to 110xc2x0 C. for 2 to 18 h, preferably 2 to 3 h. A compound (VI) is obtained by a usual post-treatment.
(Step 3)
This step is a process of obtaining a compound (VII) by removing the protecting group of carboxyl of a compound (VI). It may be carried out in accordance with a usual method as described in xe2x80x9cProtective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons)xe2x80x9d and the like.
The term xe2x80x9cthe compounds of the present inventionxe2x80x9d herein used includes a pharmaceutically acceptable salt and a solvate thereof. For example, a salt with an alkali metal (e.g., lithium, sodium, and potassium), an alkaline earth metal (e.g., magnesium and calcium), an ammonium, an organic base, an amino acid, a mineral acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or an organic acid (e.g., acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid) and a solvate of them with a solvent are examplified. A hydrate is preferable as a solvat. These salts and solvates can be formed by usual methods. A hydrate may coordinate with an arbitrary number of water molecules.
The present invention includes the prodrug of a compound of the present invention. Prodrug is a derivative of the compound of the present invention having a group which can be decomposed chemically or metabolically, and such prodrug is converted to a pharmaceutically active compound of the present invention by means of solvolysis or by placing the compound in vivo under a physiological condition. The selection method and the process method of an appropriate prodrug derivative are described in the literature such as Design of Prodrugs, Elsevier, Amsterdam 1985. When the compounds of the present invention have a carboxyl group, an ester derivative prepared by reacting a basal acid compound with a suitable alcohol or an amide prepared by reacting a basal acid compound with a suitable amine are exemplified as prodrugs. Particularly preferred esters as prodrugs are methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, morpholinoethyl ester, N,N-diethylglycolamido ester, and the like. When the compounds of the present invention have a hydroxy group, an acyloxy derivative prepared by reacting with a suitable acyl halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred acyloxy derivatives as prodrugs are xe2x80x94OCOC2H5, xe2x80x94OCOtxe2x80x94Bu, xe2x80x94OCOC15H31, xe2x80x94OCO(m-COONa-Ph), xe2x80x94OCOCH2CH2COONa, xe2x80x94OCOCH(NH2)CH3, and xe2x80x94OCOCH2N(CH3)2, and the like. When the compounds of the present invention have an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride are exemplified as prodrugs. Particularly preferred amide derivatives as prodrugs are xe2x80x94NHCO(CH2)20CH3 and xe2x80x94NHCOCH(NH2)CH3, and the like.
The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.
The compound of the present invention has a selective MMP-2 inhibitory activity and an antitumor activity as shown in the experimental examples below.
Furthermore, the compound of the present invention has generally a relatively low percentage of binding to protein, high concentration in blood, and no inhibition of P-450 enzyme. Therefore it has good property for using as medicaments.
When the compound of the present invention is administered to a patient for treating cancer, it can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective amount of the compound of this invention is formulated by being mixed with appropriate medicinal admixture such as excipient, binder, penetrant, disintegrators, lubricant, and the like, if necessary. When parenteral injection is prepared, the compound of this invention and an appropriate carrier are sterilized to prepare it.
An appropriate dosage varies with the conditions of the patients, an administration route, their age, and their body weight. In the case of oral administration to an adult, the dosage can generally be between 0.01-100 mg/kg/day, preferably 0.1-20 mg/kg/day.
The following examples are provided to further illustrate the present invention and are not to be construed as limiting the scope thereof.
In the examples, the following abbreviations are used.
Me: methyl
Et: ethyl
n-Pr: n-propyl
i-Pr: isopropyl
n-Bu: n-butyl
i-Bu: isobutyl
t-Bu: tert-butyl
Ph: phenyl
Bn: benzyl
Indole-3-yl-methyl: Indole-3-yl-methyl
DMSO: dimethylsulfoxide